ClinVar Miner

Submissions for variant NM_080679.2(COL11A2):c.3404C>T (p.Ser1135Leu) (rs534570825)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000408369 SCV000462321 likely benign Otospondylomegaepiphyseal dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000280238 SCV000462322 likely benign Stickler Syndrome, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000335339 SCV000462323 likely benign Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000408334 SCV000462324 likely benign Fibrochondrogenesis 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000300075 SCV000462325 likely benign Weissenbacher-Zweymuller syndrome 2016-06-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000609757 SCV000731579 uncertain significance not specified 2017-10-26 criteria provided, single submitter clinical testing The p.Ser1242Leu variant in COL11A2 has been previously reported by our laborato ry in one individual with hearing loss due to an alternate etiology. It has also been reported in ClinVar (Variation ID#356389) as likely benign in individuals of unknown clinical status. This variant has been identified in 34/271854 total chromosomes across several populations by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org; dbSNP rs534570825). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, the clinical significance of the p.Ser1242Leu variant is uncertain. ACMG/AMP Criteria applied: BP5, PM2_P (Richards 2015).
GeneDx RCV000657971 SCV000779742 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing The S1242L variant has not been published as pathogenic or been reported as benign to our knowledge. The variant is observed at a frequency of 0.04% (7/18756 alleles) in individuals of East Asian background in large population cohorts (Lek et al., 2016). The S1242L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with COL11A2-related disorders (Stenson et al., 2014). Furthermore, S1242L does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL11A2 gene, where the majority of missense mutations occur (Stenson et al., 2014; Symoens et al., 2012). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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